Chemotherapy remains the mainstay for treating the millions of leprosy patients throughout the world. In recent years, it has become increasingly apparent that monotherapy is insufficient for treating lepromatous disease because of the worldwide recognition of the occurrence of drug resistance or bacterial persistence during many years of single-drug therapy. Combination chemotherapy is now recommended for treating lepromatous disease. Of the drugs employed in the past for monotherapy, dapsone (DDS), rifampin (RFM), clofazimine, and the thioamides--ethionamide and prothionamide--are the best available. Experimental studies have shown that they act independently on M. leprae and are not antagonistic. DDS remains the drug of choice as the primary agent because of its high activity, low toxicity, and miniscule cost. Many years of observations will be required before optimum drug combinations can be clinically proved. At present, little is known concerning drug interactions in man involving these agents except for limited information on DDS and RFM. We propose to define drug interactions among pairs of the above four drugs by employing rat liver microsomes and hepatocytes. The drug interactions found in vitro will be reexamined in intact rats and ultimately in leprosy patients. We also plan to synthesize long-acting prodrugs of the thioamides to improve the usefulness of these relatively short-acting, potent drugs. Metabolic disposition of single drugs and drug interactions will be determined in nude athymic rats, which hold great promise for being developed into a superior laboratory model of lepromatous leprosy. Also, studies on the mechanism of the cancer induction by DDS in male rats will be pursued to determine whether this is a species-specific phenomeon and whether interactions between current antileprosy drugs increase the iatrogenic risk in patients who generally must receive lifetime chemotherapy. A clear understanding of metabolic interactions between these drugs should provide more rationally based combinations for treatment of leprosy.